This proposal is based on recent studies demonstrating sensitization that develops along peripheral and central trigemino-vascular pathways following the induction of intracranial pain in an animal model of migraine, and subsequent human studies on the presence and extent of cutaneous allodynia during migraine, using quantitative sensory testing. Based on these studies, we proposed that migraine pain is mediated by temporary changes in the responsiveness of first order peripheral nociceptors (20% of the patients), second order brainstem neurons (80% of the patients), or supraspinal (e.g., thalamic) neurons (45% of the patients). The objective of the current proposal is to test this hypothesis using functional magnetic resonance imaging (fMRI). Specific Aims 1-3 will determine whether, during migraine attacks, innocuous stimuli of the head and forearms are capable of producing augmented fMRI signals in the spinal trigeminal nucleus and/or the thalamus compared to patients (a) exhibiting no signs of cutaneous allodynia (Specific Aim 1); (b) "restricted-peri-orbital" allodynia (Specific Aim 2); and (c)"extended whole body" allodynia (Specific Aim 3). Specific Aim 4 will correlate the development of extended allodynia during migraine with fMRI signal changes in the periaqueductal gray to determine whether decreased activity in descending modulatory pathways could contribute to central sensitization in the pathophysiology of migraine. In the preliminary clinical studies, we identified patients from each of three groups who can endure 2-4 hours of repeated sensory testing during migraine attacks. In the preliminary imaging studies we were able to show that (a) painful stimuli of the peri-orbital skin increase fMRI BOLD signal in the spinal trigeminal nucleus, and the lateral and medial thalamus; (b) innocuous stimuli, such as brush applied to allodynic skin, increase fMRI signal in the thalamus; and (c) increased fMRI signal in the PAG can be induced by noxious heat. This proposal offers a collaborative effort of expertise from the fields of pain imaging, migraine, and quantitative sensory testing to examine a new hypothesis on the pathophysiology of migraine; a neurological disorder that affects more than 35 million women and men in the US.